What Causes Low Rates of Child-Bearing in Congenital Adrenal Hyperplasia?

Abstract

Women with classical congenital adrenal hyperplasia (CAH) have relatively low fertility rates (1–4). The largest clinic population was studied by Mulaikal et al. (2) who conducted a questionnaire survey of the Johns Hopkins Hospital sample of women with classical 21-hydroxylase deficiency and obtained responses from 80 of them (71% of the eligible women; age range, 18–69 yr; mean, 33 yr), evenly split into the simple virilizing (SV) and salt-wasting (SW) forms. Half of the women were not heterosexually active. Those who were heterosexually active nevertheless appeared to have low fertility. Among the 25 SV women who reported both adequate vaginal reconstruction and heterosexual activity, the fertility rate was 60%. Only 15 became pregnant, and 13 of these gave birth (9 by cesarian section because of cephalopelvic disproportion); the other 2 had an abortion, 1 spontaneous and the other induced. Among the 15 SW women with both adequate introitus and heterosexual activity, the fertility rate was 7%. Only 1 reported a pregnancy, and that ended in an elective termination. Mulaikal et al. suggested three mechanisms underlying the low fertility in CAH women overall: 1) insufficient hormonal control of the hyperandrogenemia by glucocorticoid replacement therapy (and possibly long term effects of prenatal and postnatal androgen excess), 2) insufficient vaginal reconstruction resulting in inability to engage in coitus, and 3) absence of heterosexual activity, which in some women was associated with homosexuality. In an accompanying editorial, Federman (5) suggested potential additional factors that might contribute to the low fertility in CAH: an impaired reproductive self-image related to vaginal inadequacy and “a male psychosexuality” as a consequence of putative masculinization of the fetal brain. The purpose of the present paper is to revisit the issue, review the status of the empirical evidence, especially the role of behavioral determinants, and suggest additional hormone-related psychological factors that may contribute to the low fertility rates of CAH women. The most widely recognized cause of the low rate of fertility among CAH women remains nonoptimal hormonal control. Ovulatory failure secondary to steroid excess is an important barrier to conception in many CAH women. There is considerable evidence suggesting that the steroid excess is not just an outcome of ACTH oversecretion (6). Among the other contributing factors appear to be 1) a mild degree of ACTH hyperresponsiveness to CRH; 2) altered enzyme kinetics, namely reduced catalytic efficiency of the mutated 21-hydroxylase with resulting increases in the precursor hormones progesterone and 17-hydroxyprogesterone even in the presence of excess glucocorticoid administration; 3) overactivation of the renin-angiotensin-aldosterone axis with ensuing stimulation of adrenocortical biosynthesis; and 4) alterations of the hypothalamic-pituitary-ovarian axis as indicated by abnormal gonadotropin dynamics, polycystic ovaries, and excess ovarian production of progesterone, 17-hydroxyprogesterone, and androgens (6). Consequently, new combination treatments that go beyond mere ACTH suppression are being developed to improve the overall quality of hormonal control in CAH (7). Much evidence has accumulated that implicates psychological factors in the overall reduction of fertility in women with classical CAH. Reduced heterosexual activity compared to controls has been documented in a number of studies. During adolescence, women with classical CAH as a group tend to have delayed (or absent) heterosexual milestones, such as dating, sexual initiation, and falling in love (3, 8–13). In adulthood, fewer are heterosexually active, in steady relationships, or married (2, 9–13). For all of these behaviors, it is predominantly women with the SW variant who differ from controls, much more so than those with the SV variant (4, 9, 11). Not only overt sexual activity with a partner is delayed or reduced. The frequency of sexual imagery, such as romantic/erotic fantasies and dreams, the intensity of experienced sexual motivation (drive, libido), and the capacity to fall in love also seem to be markedly lower in CAH women as a group, especially those with the SW condition, than in controls (9, 10, 12, 13), although a few CAH women complain of excessive libido, especially when untreated or when treatment lapses. The reduction of heterosexual activity is likely to stem from several causes. One is an increased rate of bi- or homosexuality in women with classical CAH, as demonstrated especially in sexual imagery such as erotic/romantic fantasies and dreams, in sexual attractions, and, to a lesser degree, in overt homosexual involvement (2, 9, 11–13, 15, 16; in a cohort of CAH with late onset of glucocorticoid replacement: 14). That several studies had negative findings (10, 17–19) is probably due to methodological factors such as inadequate assessments of sexual orientation, high propo